Neuropeptide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that activation of neuropeptide Y Y5 receptors results in hyperphagia and decreased thermogenesis.
Therefore compounds that antagonize neuropeptide Y at the Y5 receptor subtype represent an approach to the treatment of eating disorders such as obesity and hyperphagia.
The current approach is aiming at medical intervention to induce weight loss or prevention of weight gain. This is achieved by interfering with appetite control, which is mediated by the Hypothalamus, an important brain region proven to control food intake. Herein, neuropeptide Y (NPY) has been proven to be one of the strongest central mediators of food intake in several animal species. Increased NPY levels result in profound food intake. Various receptors of neuropeptide Y (NPY) have been described to play a role in appetite control and weight gain. Interference with these receptors is likely to reduce appetite and consequently weight gain. Reduction and long-term maintenance of body weight can also have beneficial consequences on con associated risk factors such as arthritis, cardiovascular diseases, diabetes and renal failure.
The invention provides compounds of formula I and pharmaceutically acceptable salts and esters thereof 
wherein
R1 is aryl or heteroaryl;
R2 is hydrogen, alkyl or cycloalkyl;
R3 is hydrogen, alkyl or cycloalkyl;
R4 is hydrogen, alkyl or cycloalkyl;
R5 is alkyl, cycloalkyl, aryl, heteroaryl;
R6 is hydrogen, alkyl or cycloalkyl;
A is xe2x80x94C(O)xe2x80x94; xe2x80x94S(O)2xe2x80x94; xe2x80x94N(R6)xe2x80x94C(O)xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94;
n is 2 to 6; and
m is zero to 2.
The compounds of formula I and their pharmaceutically acceptable salts and esters are neuropeptide ligands, for example, neuropeptide receptor antagonists and in particular, they are selective neuropeptides Y Y5 receptor antagonists.
The present invention is concerned with novel thiazole derivatives useful as neuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY) antagonists.
The invention provides compounds of formula I and pharmaceutically acceptable salts and esters thereof 
wherein
R1 is aryl or heteroaryl;
R2 is hydrogen, alkyl or cycloalkyl;
R3 is hydrogen, alkyl or cycloalkyl;
R4 is hydrogen, alkyl or cycloalkyl;
R5 is alkyl, cycloalkyl, aryl, heteroaryl;
R6 is hydrogen, alkyl or cycloalkyl;
A is xe2x80x94C(O)xe2x80x94; xe2x80x94S(O)2xe2x80x94; xe2x80x94N(R6)xe2x80x94C(O)xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94;
n is 2 to 6; and
m is zero to 2.
The compounds of formula I and their pharmaceutically acceptable salts and esters are neuropeptide ligands, for example, neuropeptide receptor antagonists and in particular, they are selective neuropeptides Y Y5 receptor antagonists.
The compounds of formula I, their salts and esters can be used in the prophylaxis or treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments comprising the said compounds, their pharmaceutically acceptable salts and esters, the use of the said compounds, salts and esters for the prophylaxis and/or therapy of illnesses, especially in the treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders such as hyperphagia and particularly obesity, and th e use of the said compounds, salts and esters for the production of medicaments for the treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
In the present description the term xe2x80x9calkylxe2x80x9d, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl and ethyl, and most preferred methyl.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C3-C8 cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl and cyclopentyl.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, signifies a group of the formula alkyl-O- in which the term xe2x80x9calkylxe2x80x9d has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, preferably methoxy and ethoxy, and most preferred methoxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more, preferably one to three substituents each independently selected from halogen, haloalkyl, amino, alkyl, alkoxy, aryloxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylenedioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, and haloalkoxy. Preferred substituents of aryl, preferably phenyl, are independently selected from halogen, trifluoromethyl, alkyl, alkoxy and haloalkoxy.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, signifies an alkyl or cycloalkyl group as previously defined, preferably an alkyl group in which one hydrogen atom has been replaced by an aryl group as previously defined. Preferred are benzyl, benzyl substituted with hydroxy, alkoxy or halogen, preferably fluorine.
The term xe2x80x9cheteroarylxe2x80x9d, alone or in combination, signifies an aromatic 5- or 6-membered ring comprising 1 to 3 atoms independently selected from nitrogen, oxygen or sulfur. Optionally, the heteroaryl ring can be substituted on one or more carbon atoms with at least one substituent selected from halogen, alkyl, alkoxy and cyano. Examples of heteroaryl rings include furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl or pyrazinyl, thienyl, isoxazolyl, oxazolyl, thiazolyl and pyrrolyl. Preferred heteroaryl rings are pyridinyl, thiophenyl and pyrazinyl which are optionally substituted with alkyl.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substituents together forming a ring, such as, for example, xe2x80x94NH2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylamino and particularly preferred primary amino.
The term xe2x80x9chalogenxe2x80x9d, alone or in combination, signifies fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine and particularly chlorine.
The term xe2x80x9chaloalkylxe2x80x9d, alone or in combination, signifies an alkyl group as previously defined, wherein one or several hydrogen atoms, preferably one to three hydrogen atoms have/has been replaced by halogen. Examples of haloalkyl groups are trifluoromethyl, pentafluoroethyl and trichloromethyl. Preferred examples are trifluoromethyl and difluoromethyl. Most preferred is trifluoromethyl.
The term xe2x80x9chaloalkoxyxe2x80x9d, alone or in combination, signifies an alkoxy group as previously defined, wherein one or several hydrogen atoms, preferably one to three hydrogen atoms have/has been replaced by halogen. A preferred example is trifluoromethoxy.
The term xe2x80x9ccyanoxe2x80x9d, alone or in combination, signifies a xe2x80x94CN group.
The term xe2x80x9cnitroxe2x80x9d, alone or in combination, signifies a xe2x80x94NO2 group.
The term xe2x80x94C(O)xe2x80x94 means a carbonyl group. 
The term xe2x80x94S(O)2xe2x80x94 means the following group: 
The term xe2x80x94N(R6)xe2x80x94C(O)xe2x80x94 means the following group: 
The term xe2x80x94Oxe2x80x94C(O)xe2x80x94 means the following group: 
Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with physiologically compatible mineral acids such hydrochloric acid, sulfuric acid or phosphoric acid; or with organic acids such as methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. Preferred is oxalic acid. The compounds of formula I with free carboxy groups can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammonium salts such as the Na, K, Ca or tertramethylammonium salt. The compound of formula I can also be present in the form of zwitterions.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term pharmaceutically acceptable salts also includes pharmaceutically acceptable solvates.
The term pharmaceutically acceptable esters of the compounds of formula I means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and; metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
In more detail, for example, the COOH groups of compounds according to formula I can be esterified. The alkyl and aralkyl esters are examples of suitable esters. The methyl, ethyl, propyl, butyl and benzyl esters are preferred esters. The methyl and ethyl esters are especially preferred. Further examples of pharmaceutically usable esters are compounds of formula I, wherein the hydroxy groups can be esterified. Examples of such esters are formate, acetate, propionate, butyrate, isobutyrate, valerate, 2-methylbutyrate, isovalerate and N,N-dimethylaminoacetate. Preferred esters are acetate and N,N-dimethylaminoacetate.
The term xe2x80x9clipase inhibitorxe2x80x9d refers to compounds which are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. For example orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin. Other lipase inhibitors include a class of compound commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al, 1994). The term xe2x80x9clipase inhibitorxe2x80x9d refers also to polymer bound lipase inhibitors for example described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they have been substituted with one or more groups that inhibit lipases. The term xe2x80x9clipase inhibitorxe2x80x9d also comprises pharmaceutically acceptable salts of these compounds. The term xe2x80x9clipase inhibitorxe2x80x9d preferably refers to orlistat.
Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986, which also discloses processes for making orlistat and U.S. Pat. No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123. Additional processes for the preparation of orlistat are disclosed in European Patent Applications Publication Nos. 185,359, 189,577, 443,449, and 524,495.
Orlistat is preferably orally administered from 60 to 720 mg per day in: divided doses two to three times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day. The subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater. Generally, it is preferred that the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat. Generally, for administering a lipase inhibitor as defined above it is preferred that treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
Orlistat can be administered to humans in conventional oral compositions, such as, tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions. Examples of carriers which can be used for tablets, coated tablets, dragxc3xa9es and hard gelatin capsules are lactose, other sugars and sugar alcohols like sorbitol, mannitol, maltodextrin, or other fillers; surfactants like sodium lauryle sulfate, Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maize starch or derivatives thereof; polymers like povidone, crospovidone; talc; stearic acid or its salts and the like. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. They can also contain still other therapeutically valuable substances. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art. Preferably, orlistat is administered according to the formulation shown in the Examples and in U.S. Pat. No. 6,004,996, respectively.
The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
In the nomenclature used in the present application the ring atoms of the thiazole ring are numbered as follows: 
wherein R1 to R5, m, n and A are defined as before. In a preferred embodiment of the present invention R2 is attached to the 5-position and the substituent xe2x80x94C(O)xe2x80x94R1 is attached to the 4-position of the thiazole ring. Particularly preferred are the compounds of formula I, wherein the substituent xe2x80x94C(O)xe2x80x94R1 is attached to the 5-position and R2 is attached to the 4-position of the thiazole ring.
Preferred are compounds of formula I, wherein R2 is hydrogen or alkyl. Particularly preferred are compounds of formula I, wherein R2 is hydrogen or methyl. Most preferred are compounds according to formula I, wherein R2 is hydrogen.
A further preferred object of the present invention are compounds of formula I, wherein R3 is hydrogen or alkyl. Particularly preferred are those compounds of formula I, wherein R3 is hydrogen.
Also a preferred object of the present invention are compounds of formula I, wherein R4 is hydrogen or alkyl. Particularly preferred are compounds according to formula I, wherein R4 is hydrogen.
Another preferred object of the present invention are compounds of formula I, wherein R5 is alkyl, cycloalkyl, phenyl, phenyl substituted with one to three substituents independently selected from halogen, alkyl, alkoxy and haloalkyl, or R5 is thiophenyl or thiophenyl substituted with alkyl, or R5 is pyridinyl or pyridinyl substituted with alkyl or R5 is pyrazinyl or pyrazinyl substituted with alkyl. Particularly preferred are compounds according to formula I, wherein R5 is n-butyl, tert.butyl, cyclohexyl, thiophenyl, phenyl or phenyl substituted with one to three substituents independently selected from methyl, ethyl, methoxy, fluoro, chloro and trifluoromethyl. Further particularly preferred are compounds according to formula I, wherein R5 is thiophenyl or phenyl optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halogen and haloalkyl.
Preferred are compounds according to formula I, wherein R5 is thiophenyl or phenyl both optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and nitro.
A further preferred object of the present invention are compounds according to formula I, wherein R6 is hydrogen.
Also preferred are compounds of formula I, wherein R1 is pyridinyl or pyridinyl substituted with alkyl, or R1 is thiophenyl or thiophenyl substituted with alkyl or R1 is phenyl or phenyl substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl or R1 is pyrazinyl or pyrazinyl substituted with alkyl. Particularly preferred are compound according to formula I, wherein R1 is pyridinyl, phenyl or phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen and haloalkyl. Very preferred are compounds of formula I, wherein R1 is pyridinyl or phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen and haloalkyl.
A further particularly preferred object of the present invention are compounds according to formula I, wherein A is xe2x80x94S(O)2xe2x80x94
Another preferred embodiment of the present invention are compounds of formula I, wherein A is xe2x80x94C(O)xe2x80x94.
Further preferred are compounds of formula I, wherein A is xe2x80x94N(R6)xe2x80x94C(O)xe2x80x94.
Also preferred are compounds of formula I, wherein A is xe2x80x94Oxe2x80x94C(O)xe2x80x94.
Likewise preferred are compounds of formula I, wherein n is 3 to 5. Particularly preferred are compounds of formula I, wherein n is 3. Further particularly preferred are compounds of formula I, wherein n is 5.
Preferred compounds of formula I are those, wherein m is zero or 1. Particularly preferred are those compounds of formula I, wherein m is zero. A further very preferred embodiment of this invention are compounds of formula I, wherein A is xe2x80x94S(O)2xe2x80x94 and m is zero.
Examples of preferred compounds of formula I are:
1. 2-Fluoro-N-{3-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
2. 2-Methoxy-5-methyl-N-{3-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
3. 2-Methoxy-5-methyl-N-{3-[5-(pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
4. 2-Methoxy-5-methyl-N-{3-[5-(pyridine-4-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
5. 2-Fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
6. 4-Methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
7. Thiophene-2-sulfonic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
8. 2-Methoxy-5-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
9. 4-Fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
10. 2-Methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
11. 3-Fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
12. 2-Chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide
13. N-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
14. 3-Methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
15. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-2-fluoro-benzenesulfonamide
16. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-4-methoxy-benzenesulfonamide
17. Thiophene-2-sulfonic acid {3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-amide
18. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-2-methoxy-5-methyl-benzenesulfonamide
19. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-4-fluoro-benzenesulfonamide
20. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-2-methyl-benzenesulfonamide
21. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-fluoro-benzenesulfonamide
22. 2-Chloro-N-{3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide
23. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
24. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-methoxy-benzenesulfonamide
25. {3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester
26. {3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester
27. {3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester
28. {3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester
29. Cyclohexanecarboxylic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
30. Cyclohexanecarboxylic acid {3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
31. Pentanoic acid [3-(5-benzoyl-thiazol-2-ylamino)-propyl]-amide
32. Pentanoic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
33. Pentanoic acid {3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
34. Pentanoic acid {3-[5-(2-fluoro-benzoyl)-thiazol-2-ylamino]-propyl}-amide
35. Pentanoic acid {3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-amide
36. N-[3-(5-Benzoyl-thiazol-2-ylamino)-propyl]-2-(4-chloro-phenyl)-acetamide
37. 2-(4-Chloro-phenyl)-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-acetamide
38. 2-(4-Chloro-phenyl)-N-{3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-acetamide
39. Thiophene-2-carboxylic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
40. Thiophene-2-carboxylic acid {3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
41. Thiophene-2-carboxylic acid {3-[5-(2-fluoro-benzoyl)-thiazol-2-ylamino]-propyl}-amide
42. Thiophene-2-carboxylic acid {3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-amide
43. N-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-2-fluoro-benzamide
44. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-2-fluoro-benzamide
45. 3-Fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
46. N-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-fluoro-benzamide
47. 3-Fluoro-N-{3-[5-(2-fluoro-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
48. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-fluoro-benzamide
49. 4-Fluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
50. N-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-fluoro-benzamide
51. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-4-fluoro-benzamide
52. N-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
53. N-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
54. N-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
55. N-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-methoxy-benzamide
56. N-[3-(5-Benzoyl-thiazol-2-ylamino)-propyl]-2-methoxy-benzamide
57. N-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-2-methoxy-benzamide
58. 4-Chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
59. 4-Chloro-N-{3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
60. Cyclohexanecarboxylic acid {3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
61. Cyclohexanecarboxylic acid {3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-amide
62. Pentanoic acid {3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
63. Pentanoic acid {3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-amide
64. Pentanoic acid {3-[5-(2-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-amide
65. Pentanoic acid {3-[5-(3-methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-propyl}-amide
66. 2-(4-Chloro-phenyl)-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-acetamide
67. 2-(4-Chloro-phenyl)-N-{3-[5-(3-methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-propyl}-acetamide
68. 2-(4-Chloro-phenyl)-N-{3-[5-(3-methyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-propyl}-acetamide
69. Thiophene-2-carboxylic acid {3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
70. Thiophene-2-carboxylic acid {3-[5-(3-methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-propyl}-amide
71. 2-Fluoro-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
72. 2-Fluoro-N-{3-[5-(3-methyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
73. 3-Fluoro-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
74. 3-Fluoro-N-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
75. 3-Fluoro-N-{3-[5-(3-methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
76. 3-Fluoro-N-{3-[5-(3-methyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
77. 4-Fluoro-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
78. 4-Fluoro-N-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
79. 4-Fluoro-N-{3-[5-(3-methyl-pyridine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
80. 4-Fluoro-N-{3-[5-(3-methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
81. N-{3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
82. N-{3-[5-(4-Methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
83. 4-Methoxy-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
84. 4-Methoxy -N-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}benzamide
85. 2-Methoxy-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
86. 4-Chloro-N-{3-[5-(2-trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
87. 4-Chloro-N-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
88. 4-Chloro-N-{3-[5-(2-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzamide
89. 1-[3-(5-Benzoyl-thiazol-2-ylamino)-propyl]-3-cyclohexyl-urea
90. 1-Cyclohexyl-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
91. 1-Cyclohexyl-3-{3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
92. 1-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-cyclohexyl-urea
93. 1-[3-(5-Benzoyl-thiazol-2-ylamino)-propyl]-3-butyl-urea
94. 1-Butyl-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
95. 1-Butyl-3-{3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
96. 1-Butyl-3-{3-[5-(2-fluoro-benzoyl)-thiazol-2-ylamino]-propyl}-urea
97. 1-Butyl-3-{3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-urea
98. 1-(2-Methoxy-phenyl)-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
99. 1-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-(2-methoxy-phenyl)-urea
100. 1-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-(2-methoxy-phenyl)-urea
101. 1-(2-Fluoro-phenyl)-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
102. 1-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-(2-fluoro-phenyl)-urea
103. 1-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-(2-fluoro-phenyl)-urea
104. 1-(3-Fluoro-phenyl)-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
105. 1-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-(3-fluoro-phenyl)-urea
106. 1-(4-Fluoro-phenyl)-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
107. 1-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-(4-fluoro-phenyl)-urea
108. 1-[3-(5-Benzoyl-thiazol-2-ylamino)-propyl]-3-(2-chloro-benzyl)-urea
109. 1-(2-Chloro-benzyl)-3-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
110. 1-(2-Chloro-benzyl)-3-{3-[5-(2-ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
111. 1-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-(2-chloro-benzyl)-urea
112. 1-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-phenyl-urea
113. 1-{3-[5-(2-Ethyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-phenyl-urea
114. 1-{3-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-propyl}-3-phenyl-urea
115. 1-Butyl-3-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-urea
116. 1-{3-[5-(4-Methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-3-phenyl-urea
117. 1-Cyclohexyl-3-{3-[5-(3-methyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-propyl}-urea
118. 1-Cyclohexyl-3-{3-[5-(3-methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-propyl}-urea
119. 4-Fluoro-N-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
120. 4-Fluoro-N-{3-[5-(3-methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
121. 2-Methoxy-5-methyl-N-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
122. 2-Methoxy-5-methyl-N-{3-[5-(3-methyl-pyrazine-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
123. 2-Methoxy-5-methyl-N-{3-[5-(3-methyl-thiophene-2-carbonyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
124. 1-(4-Methoxy-phenyl)-3-{3-[5-(4-methyl-pyridine-3-carbonyl)-thiazol-2-ylamino]-propyl}-urea
125. {3-[4-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester
126. N-{3-[4-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
127. 2-Fluoro-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
128. 3,5-Dimethoxy-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzamide
129. Pentanoic acid {3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
130. 1-{3-[4-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-3-thiophen-2-yl-urea
131. 1-(2-Fluoro-phenyl)-3-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-urea
132. 2-Methyl-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
133. 4-Fluoro-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
134. 3-Methoxy-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
135. 4-Methoxy-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
136. N-{3-[4-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
137. 2-Chloro-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide
138. Thiophene-2-sulfonic acid {3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
139. 3-Fluoro-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
140. 2-Methoxy-5-methyl-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
141. 2,5-Dimethoxy-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
142. 2-Fluoro-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
143. 4-Methoxy-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
144. Thiophene-2-sulfonic acid {5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-amide
145. 2-Methoxy-5-methyl-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
146. 4-Fluoro-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
147. 2-Methyl-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
148. 3-Fluoro-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
149. 2-Chloro-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-5-trifluoromethyl-benzenesulfonamide
150. N-{5-[5-(Pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
151. 3-Methoxy-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
152. 2-Fluoro-N-{5-[5-(pyridine-4-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
153. 2-Methoxy-5-methyl-N-{5-[5-(pyridine-4-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
154. 2-Fluoro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
155. 4-Methoxy-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
156. Thiophene-2-sulfonic acid {5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-amide
157. 2-Methoxy-5-methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
158. 4-Fluoro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
159. 2-Methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
160. 3-Fluoro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
161. 2-Chloro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-5-trifluoromethyl-benzenesulfonamide
162. N-{5-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
163. 3-Methoxy-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
164. N-{5-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-fluoro-benzenesulfonamide
165. N-{5-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-4-methoxy-benzenesulfonamide
166. Thiophene-2-sulfonic acid {5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-amide
167. N-{5-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-methoxy-5-methyl-benzenesulfonamide
168. N-{5-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-4-fluoro-benzenesulfonamide
169. N-{5-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-methyl-benzenesulfonamide
170. N-{5-[5-(2-Chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-3-fluoro-benzenesulfonamide
171. 2-Chloro-N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-5-trifluoromethyl-benzenesulfonamide
172. N-{5-[4-Methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
173. 2-Methyl-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
174. 2-Fluoro-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
175. 3-Fluoro-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
176. 4-Fluoro-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
177. 2-Methoxy-5-methyl-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
178. 3-Methoxy-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
179. 4-Methoxy-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
180. Thiophene-2-sulfonic acid {2-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-ethyl}-amide
181. 2,5-Dimethoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
182. Thiophene-3-sulfonic acid {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-amide
183. 2,5-Dimethoxy-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
184. Thiophene-3-sulfonic acid {2-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-ethyl}-amide
185. 2,5-Dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
186. 5-Chloro-2-methoxy-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
187. 2-Methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
188. 5-Fluoro-2-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
189. 2-Chloro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-5-trifluoromethyl-benzenesulfonamide
190. 2,5-Dimethyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
191. N-{3-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-trifluoromethoxy-benzenesulfonamide
192. 4-Fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
193. 2,4-Difluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
194. N-{5-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-4-trifluoromethoxy-benzenesulfonamide
195. 2-Chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-trifluoromethyl-benzenesulfonamide
196. 2-Fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
197. 5-Chloro-thiophene-2-sulfonic acid {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-amide
198. 2-Chloro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-4-trifluoromethyl-benzenesulfonamide
199. Thiophene-3-sulfonic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
200. 5-Fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
201. 3-Fluoro-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
202. 2-Methoxy-5-methyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
203. Thiophene-3-sulfonic acid {5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-amide
204. 5-Fluoro-2-methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
205. 5-Chloro-2-methoxy-N-{2-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-ethyl}-benzenesulfonamide
206. 2,4-Difluoro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
207. 2,5-Dimethyl-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
208. 2,5-Dimethoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
209. 2,4-Difluoro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide
210. 5-Chloro-thiophene-2-sulfonic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
211. 4-Methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
212. 5-Chloro-2-methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
213. 5-Chloro-thiophene-2-sulfonic acid {5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-amide
214. Thiophene-2-sulfonic acid {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-amide
215. 3-Methoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide
216. N-{4-[5-(2-Methyl-benzoyl)-thiazol-2-ylamino]-butyl}-4-trifluoromethoxy-benzenesulfonamide
217. Thiophene-2-sulfonic acid methyl-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
218. 3-Methoxy-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
219. 2-Chloro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-trifluoromethyl-benzenesulfonamide
220. 2,N-Dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
221. 5-Fluoro-2,N-dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
222. 2-Chloro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide
223. 4-Fluoro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
224. 2,4-Difluoro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
225. 2-Fluoro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
226. 5-Chloro-thiophene-2-sulfonic acid methyl-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide
227. 3-Fluoro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
228. 2-Methoxy-5,N-dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
229. 4-Chloro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
230. 2,5,N-Trimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
231. N-Methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-nitro-benzenesulfonamide
232. 4-Methoxy-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
233. 5-Chloro-2-methoxy-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide
Examples of particularly preferred compounds of formula I are:
Thiophene-2-sulfonic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
2-methoxy-5-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide;
2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide;
thiophene-2-sulfonic acid {3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
N-{3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-2-methoxy-5-methyl-benzenesulfonamide;
2-chloro-N-{3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide;
2-chloro-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide;
2-methoxy-5-methyl-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide;
2-methoxy-5-methyl-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
4-methoxy-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-methoxy-5-methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
3-fluoro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-chloro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-5-trifluoromethyl-benzenesulfonamide;
N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-fluoro-benzenesulfonamide;
N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-methoxy-5-methyl-benzenesulfonamide;
N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-methyl-benzenesulfonamide;
2-methoxy-5-methyl-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-trifluoromethyl-benzenesulfonamide;
5-fluoro-2-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide;
2,5-dimethoxy-N-{4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-benzenesulfonamide;
5-chloro-thiophene-2-sulfonic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
thiophene-2-sulfonic acid {4-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-butyl}-amide;
thiophene-2-sulfonic acid methyl-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
2,N-dimethyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide;
5-chloro-thiophene-2-sulfonic acid methyl-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
4-chloro-N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide and
N-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-4-nitro-benzenesulfonamide.
Examples of particularly preferred compounds of formula I are:
Thiophene-2-sulfonic acid {3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
2-methoxy-5-methyl-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide;
2-chloro-N-{3-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide;
thiophene-2-sulfonic acid {3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-amide;
N-{3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-2-methoxy-5-methyl-benzenesulfonamide;
2-chloro-N-{3-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide;
2-chloro-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-5-trifluoromethyl-benzenesulfonamide;
2-methoxy-5-methyl-N-{3-[4-(2-methyl-benzoyl)-thiazol-2-ylamino]-propyl}-benzenesulfonamide;
2-methoxy-5-methyl-N-{5-[5-(pyridine-2-carbonyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
4-methoxy-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-methoxy-5-methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-methyl-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
3-fluoro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-benzenesulfonamide;
2-chloro-N-{5-[5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-5-trifluoromethyl -benzenesulfonamide;
N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-fluoro-benzenesulfonamide;
N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-methoxy-5-methyl-benzenesulfonamide;
N-{5-[5-(2-chloro-benzoyl)-thiazol-2-ylamino]-pentyl}-2-methyl-benzenesulfonamide; and
2-methoxy-5-methyl-N-{5-[4-methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}benzenesulfonamide.
Processes for the manufacture of compounds of formula I are an object of the invention.
The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following Schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those in the art. The substituents and indices used in the following description of the processes have the significance given above unless indicated to the contrary.
Compounds of general formula IH (R2 means hydrogen) can be prepared according to scheme 1 as follows:
a) Bis amino derivatives IA, either commercially available or prepared from commercially available precursors by methods taught in the art, are mono-protected with a suitable protecting group (PG i.e. Boc, Fmoc, and the like), provided that PG has no adverse effect on the reaction or on the reagents involved in the synthetic route, by reaction of IA with preferably Boc2O, preferably in the presence or the absence of a base such as triethylamine, diisopropylethylamine, and the like, preferably in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, or dioxane, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice. (literature: J. Med. Chem., 32(2), 391-6; 1989).
b) Thioureas can be prepared from suitable starting materials according to methods known in the art. The elaboration of the thiourea-moiety in ID starting from an amino functionality, like in IB can be affected by methods described in literature. For example mono-protected derivatives IB are condensed with benzoyl isothiocyanate in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, or dioxane, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the protected urea derivatives IC. (literature: Organic Letters, 2(20), 3237-3240;2000). The urea derivatives IC are subjected to basic cleavage conditions such as K2CO3 aq., and the like, in a solvent such as methanol, and the like, to liberate the urea functionality and access ureas ID. (for reaction conditions described in literature affecting such a reaction see for example: J. Med. Chem., 32(8), 1963-70; 1989).
c) The conversion of the liberated ureas ID to Dimethylaminomethylene-thioureido derivatives IE (R2 means hydrogen) was affected by reaction of derivatives ID with N,N-Dimethylformamide dimethyl acetal either neat or in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, or dioxane, DMF and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the protected urea derivatives IC. For reaction conditions described in literature affecting such a reaction see for example: Heterocycles, 11, 313-18; 1978.
d) Dimethylaminomethylene-thioureido derivatives IE can be converted to thiazole derivatives IF (R2 means hydrogen) by reaction of IE with xcex1-bromoketones (a known compound or compound prepared by known methods. The source for xcex1-Bromoketones employed is indicated as appropriate) in a solvent such as ethanol, and the like, in the presence or the absence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, or dioxane, methanol, ethanol and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the protected thiazole derivatives IF. For reaction conditions described in literature affecting such a reaction see for example: J. Heterocycl. Chem., 16(7), 1377-83; 1979. The resulting compound of formula IF is a compound of the present invention and may be the desired product; alternatively it may be subjected to consecutive reactions.
e) Cleavage of the protecting group PG such as Boc, Fmoc, and the like from thiazole derivatives IF to access free amines IG or various salts thereof, IF is in the case PG means Boc subjected to suitable reaction conditions like acidic cleavage. There is no particular restriction on the nature of the acid used in this stage, and any acid commonly used in this type of reaction may equally be employed here. Examples of such acids include: HCl, TFA, and the like in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dioxane, water, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IG. For conditions described in literature affecting the cleavage of a protecting group see for example: Protecting Groups, Kocienski, P. Thieme Verlag New York 1994.
f) Sulfonamides, amides, carbamates and ureas can be prepared from suitable starting materials according to methods known in the art. The conversion of the amino-moiety in IG to access sulfonamides, amides, carbamates and can be affected by methods described in literature. For example the conversion of the amine derivatives IG or their respective salts to access compounds of the general formula IH is affected by reaction of IG with suitable acid chlorides, sulfonyl chlorides, isocyanates, chloroformates, or carbonate esters (compounds known or compound prepared by known methods) respectively in a solvent like dichloromethane and in the presence or the absence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: chloroform, or dioxane, THF, and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IH. For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley and Sons, New York, N.Y. 1999. 
Compounds of general formula IIE (R2 means alkyl or cycloalkyl) can be prepared according to scheme 2 as follows:
a) Thioisocyanates can be prepared from suitable starting materials according to methods known in the art. The elaboration of the thioisocyanate-moiety in IIA (R3 means hydrogen) starting from an amino functionality, can be affected by methods described in literature. For example compounds of the general formula IB (PG for example Boc, Fmoc, and such like) are condensed with carbondisulfide, neat or in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, or dioxane, THF and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield an intermediate which is reacted with cyanamide in one-pot or after isolation of the intermediate. Elaboration of the thioisocanate derivatives IIA (R3 means hydrogen) is affected by addition of a base such as pyridine, or the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, or dioxane, THF and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include pyridine, triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the thioisocyanate derivatives IIA. For reaction conditions described in literature affecting such a reaction see for example: Journal of Organic Chemistry, 65(19), 6069-6072; 2000.
b) Thioureido derivatives can be prepared from suitable starting materials according to methods known in the art. The elaboration of the thioisocyanate-moiety in IIA (R3 means hydrogen) to a thioureido-moiety can be affected by methods described in literature. For example compounds of the general formula IIA are condensed with an amidine or their salts (R2 means alkyl, cycloakly), a known compound or compound prepared by known methods, in a solvent such as THF, or the like, and a base,:such as NaOH, or the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, dioxane, THF and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include NaOHaq., KOHaq, NEt3, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction from 0xc2x0 C. to heating to reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the thioureido derivatives IIB. For reaction conditions described in literature affecting such a reaction see for example: C. R. Seances Acad. Sci., Ser. 2, 294(19), 1183-6; 1982.
c) Dimethylaminomethylene-thioureido derivatives IIB can be converted to thiazole derivatives IIC (R2 means alkyl, cycloalkyl) by reaction of IIB with xcex1-bromoketones (a known compound or compound prepared by known methods) in a solvent such as ethanol, and the like, in the presence or the absence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, DMF, dioxane, methanol, ethanol and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type.of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the protected thiazole derivatives IIC (R3 means H). For reaction conditions described in literature affecting such a reaction see for example: Org. Chem., 65(21), 7244-7247; 2000. The resulting compound of formula IIC (R3 means H) is a compound of the present invention and may be the desired product; alternatively it may be subjected to consecutive reactions. Introduction of R3 means alkyl or cycloalkyl can be affected by reductive amination of IIC with the respective aldehyde under reducing conditions in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, dioxane, THF, and the like. There is no particular restriction on the nature of the reducing agent used in this stage, and any reducing agent commonly used in this type of reaction may equally be employed here. Examples of such reducing agents include NaBH4, NaCNBH3, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the protected thiazole derivatives IIC (R3 means alkyl or cycloalkyl). For reaction conditions described in literature affecting a reductive amination see for example: Reductive amination in: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley and Sons, New York, N.Y. 1999. The resulting compound of formula IIC (R3 means alkyl or cycloalkyl) is a compound of the present invention and may be the desired product; alternatively it may be subjected to consecutive reactions.
d) Cleavage of the protecting group such as Boc and Fmoc, and the like from thiazole derivatives IIC to access free amines IID or various salts thereof, IIC is subjected to suitable reaction conditions like for example acidic cleavage for the cleavage of the Boc-protecting group. There is no particular restriction on the nature of the acid used in this stage, and any acid commonly used in this type of reaction may equally be employed here. Examples of such acids include: HCl, TFA, and the like in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dioxane, water, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IID. For conditions described in literature affecting the cleavage of a protecting group see for example: Protecting Groups, Kocienski, P. Thieme Verlag New York 1994.
e) Sulfonamides, amides, carbamates and ureas can be prepared from suitable starting materials according to methods known in the art. The conversion of the amino-moiety in IID to access sulfonamides, amides, carbamates and ureas can be affected by methods described in literature. For example the conversion of the amine derivatives IID or their respective salts to access compounds of the general formula IIE is affected by reaction of IID with suitable acid chlorides, sulfonyl chlorides, isocyanates, chloroformates, or carbonate esters (compounds known or compound prepared by known methods) respectively in a solvent like dichloromethane and in the presence or the absence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: chloroform, dioxane, THF, and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IIE. For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley and Sons, New York, N.Y. 1999. 
Compounds of general formula IIID can be prepared according to scheme 3 as follows:
a) Aminothiazoles can be prepared from suitable starting materials according to methods known in the art. The conversion of a thiourea-moiety like in derivatives of the general formula ID can be affected by methods described in literature. For example thiourea derivatives of the general formula ID are reacted with a-bromo-diketones of the general formula IIIA (compounds known or compounds prepared by known methods) in a solvent such as methanol, or the like, in the presence or the absence of a base, such as triethylamine, or the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, dioxane, ethanol, THF, and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IIIB. For reaction conditions described in literature affecting such reactions see for example: J. Heterocycl. Chem., 16(7), 1377-83; 1979.
b) Cleavage of the protecting group such as Boc and Fmoc, and the like from thiazole derivatives IIIB to access free amines IIIC or various salts thereof, IIIB is subjected to suitable reaction conditions like for example acidic cleavage for the cleavage of the Boc-protecting group. There is no particular restriction on the nature of the acid used in this stage, and any acid commonly used in this type of reaction may equally be employed here. Examples of such acids include: HCl, TFA, and the like in a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dioxane, water, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IIIC. For conditions described in literature affecting the cleavage of a protecting group see for example: Protecting Groups, Kocienski, P. Thieme Verlag New York 1994.
c) Sulfonamides, amides, carbamates and ureas can be prepared from suitable starting materials according to methods known in the art. The conversion of the amino-moiety in IIIC to access sulfonamides, amides, carbamates and ureas can be affected by methods described in literature. For example the conversion of the amine derivatives IIIC or their respective salts to access compounds of the general formula IIID is affected by reaction of IIIC with suitable acid chlorides, sulfonyl chlorides, isocyanates, chloroformates, or carbonate esters (compounds known or compound prepared by known methods) respectively in a solvent, such as dioxane and methanol, and such like, and in the presence or the absence of a base, such as triethylamine, or the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: dichloromethane, chloroform, dioxane, THF, and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield thiazole derivatives IIID. For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley and Sons, New York, N.Y. 1999. 
The conversion of a compound of formula I into a pharmaceutically acceptable salt can be carried out by treatment of such a compound with an inorganic acid, for example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., or with an organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
The conversion of compounds of formula I into pharmaceutically usable esters or amides can be carried out e.g. by treatment of suited amino or hydroxyl groups present in the molecules with an carboxylic acid such as acetic acid, with a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or N,N-dicyclohexylcarbodiimide (DCC) to produce the carboxylic ester or carboxylic amide.
Preferred intermediates are:
Example H
[2-(3-Amino-propylamino)-thiazol-5-yl]-phenyl-methanone; hydrochloride
Example I
[2-(3-Amino-propylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride
Example J
[2-(3-Amino-propylamino)-thiazol-5-yl]-(2-ethyl-phenyl)-methanone; hydrochloride
Example K
[2-(3-Amino-propylamino)-thiazol-5-yl]-(2-fluoro-phenyl)-methanone; hydrochloride
Example L
[2-(3-Amino-propylamino)-thiazol-5-yl]-(2-chloro-phenyl)-methanone; hydrochloride
Example M
[2-(3-Amino-propylamino)-thiazol-5-yl]-(2-trifluoromethyl-phenyl)-methanone; hydrochloride
Example N
[2-(3-Amino-propylamino)-thiazol-5-yl]-(4-methyl-pyridin-3-yl)-methanone; hydrochloride
Example O
2-(3-Amino-propylamino)-thiazol-5-yl]-(3-methyl-pyridin-2-yl)-methanone; hydrochloride
Example P
[2-(3-Amino-propylamino)-thiazol-5-yl]-(2-methyl-pyridin-3-yl)-methanone; hydrochloride
Example Q
[2-(3-Amino-propylamino)-thiazol-5-yl]-(3-methyl-pyrazin-2-yl)-methanone; hydrochloride
Example R
[2-(3-Amino-propylamino)-thiazol-5-yl]-(3-methyl-thiophen-2-yl)-methanone; hydrochloride
Example S
[2-(5-Amino-pentylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride
Example T
[2-(5-Amino-pentylamino)-thiazol-5-yl]-pyridin-2-yl-methanone; hydrochloride
Example U
[2-(5-Amino-pentylamino)-thiazol-5-yl]-pyridin-4-yl-methanone; hydrochloride
Example V
[2-(5-Amino-pentylamino)-thiazol-5-yl]-(2-chloro-phenyl)-methanone; hydrochloride
Example Y
{3-[4-(2-Methyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester
Example Z
[2-(3-Amino-propylamino)-thiazol-4-yl]-o-tolyl-methanone; hydrochloride
Example AC
{5-[4-Methyl-5-(2-methyl-benzoyl)-thiazol-2-ylamino]-pentyl}-carbamic acid tert-butyl ester
Example AD
[2-(5-Amino-pentylamino)-4-methyl-thiazol-5-yl]-o-tolyl-methanone hydrochloride
Also an object of the invention are compounds described above for the production of medicaments for the prophylaxis and therapy of illnesses which are caused by disorders associated with the NPY receptor, particularly for the production of medicaments for the prophylaxis and therapy of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
Likewise an object of the invention are pharmaceutical compositions containing a compound of formula I described above and a therapeutically inert carrier.
An object of the invention is also the use of the compounds described above for the production of medicaments, particularly for the treatment and prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
A preferred object of the invention is the use of compounds as described before for the production of medicaments for the treatment of obesity.
A further object of the invention comprises compounds which are manufactured according to one of the described processes.
A further object of the invention is a method for the treatment and prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity whereby an effective amount of a compound described above is administered.
Particularly preferred is a method for the treatment of obesity whereby an effective amount of a compound as mentioned above is administered.
According to a further aspect of the invention there is provided a method of treatment of obesity in a human in need of such treatment which comprises administration to the human a therapeutically effective amount of a compound according to formula I and a therapeutically effective amount of a lipase inhibitor, particularly preferred, wherein the lipase inhibitor is orlistat. Also subject of the present invention is the mentioned method, wherein the administration is simultaneous, separate or sequential.
A further preferred embodiment of the present invention is the use of a compound of the formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor, particularly preferred, wherein the lipase inhibitor is orlistat.
A preferred process for the preparation of a compound of formula I comprises the reaction of a compound of formula (II) 
in the presence of a compound of formula (III) 
wherein R1 to R5, A, m and n are defined as before and, wherein X means e.g. chloro or bromo.
The compounds of formula I described above for use as therapeutically active substances are a further object of the invention.
Also an object of the invention are compounds described above for the production of medicaments for the prophylaxis and therapy of illnesses which are caused by disorders associated with the NPY receptor, particularly for the production of medicaments for the prophylaxis and therapy of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
Likewise an object of the invention is a pharmaceutical composition comprising a compound of formula I described above and a therapeutically inert carrier. Preferred is this composition comprising further a therapeutically effective amount of a lipase inhibitor. Particularly preferred is the above composition, wherein the lipase inhibitor is orlistat.
An object of the invention is also the use of the compounds described above for the production of medicaments, particularly for the treatment and prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
A further object of the invention comprises compounds which are manufactured according to one of the described processes.
A further object of the invention is a method for the treatment and prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity whereby an effective amount of a compound described above is administered.
According to a further aspect of the invention there is provided a method of treatment of obesity in a human in need of such treatment which comprises administration to the human a therapeutically effective amount of a compound according to formula I and a therapeutically effective amount of a lipase inhibitor, particularly preferred, wherein the lipase inhibitor is orlistat. Also subject of the present invention is the mentioned method, wherein the administration is simultaneous, separate or sequential.
A further preferred embodiment of the present invention is the use of a compound of the formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor, particularly preferred, wherein the lipase inhibitor is orlistat.
Cloning of Mouse NPY5 Receptor cDNAs:
The full-length cDNA encoding the mouse NPY5 (mNPY5) receptor was amplified from mouse brain cDNA using specific primers, designed based on the published sequence, and Pfu DNA-Polymerase. The amplification product was subcloned into the mammalian expression vector pcDNA3 using EcoRI and XhoI restriction sites. Positive clones were sequenced and one clone, encoding the published sequence (see Borowsky, B., et al., Molecular biology and pharmacology of multiple NPY Y5 receptor species homologs, Regul. Pept. (1998) 75-76:45-53) was selected for generation of stable cell clones.
Stable Transfection:
Human embryonic kidney 293 (HEK293) cells were transfected with 10 xcexcg mNPY5 DNA using the lipofectamine reagent (Gibco BRL) according to the manufacturer""s instruction. Two days after transfection, geneticin selection (1 mg/ml) was initiated and several stable clones were isolated. One clone was further used for pharmacological characterization.
Radioligand Competition Binding:
Human embryonic kidney 293 cells (HEK293), expressing recombinant mouse NPY5-receptor (mNPY5) were broken by three freeze/thawing cycles in hypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCl2), homogenized and centrifuged at 72,000xc3x97g for 15 min. The pellet was washed twice with 75 mM Tris buffer, pH 7.4, containing 25 mM MgCl2 and 250 mM sucrose, 0.1 mM phenylmethylsulfonylfluoride and 0.1 mM 1,10-pheneanthrolin, resuspended in the same buffer and stored in aliquots at xe2x88x9280xc2x0 C. Protein was determined according to the method of Lowry using bovine serum albumine (BSA) as a standard.
Radioligand competition binding assays were performed in 250 xcexcl 25 mM Hepes buffer (pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 1% bovine serum albumine, and 0.01% NaN3 containing 5 xcexcg protein, 100 pM [125I]labelled peptide YY (PYY) and 10 xcexcL DMSO containing increasing amounts of unlabeled test compounds. After incubation for 1 h at 22xc2x0 C., bound and free ligand are separated by filtration over glass fibre filters. Non specific binding is assessed in the presence of 1 xcexcM unlabelled PYY. Specific binding is defined as the difference between total binding and non specific binding. IC50 values are defined as the concentration of antagonist that displaces 50% of the binding of [125I]labelled neuropeptide Y. It is determined by linear regression analysis after logit/log transformation of the binding data.
Results obtained in the foregoing test using representative compounds of the invention as the test compounds are shown in the following table:
Compounds as described above have IC50 values below 1000 nM; more preferred compounds have IC50 values below 100 nM. Most preferred compounds have IC50 values below 10 nM. These results have been obtained by using the foregoing test.
The in vitro assay published by D. Lachammer, et al., Reversal of NPY inhibition of forkelin-stimulated cAMP production, J. Biol. Chem. (1992) 267:10935-8, and M. H. Norman et al., J. Med. Chem. (2001) 44:2344-56, was used to confirm that the compounds of the present invention are antagonists of neuropeptide Y.
The compounds of formula I and their pharmaceutically usable salts, solvates and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations which include pharmaceutically acceptable carriers which are therapeutically inert). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
The compounds of formula I and their pharmaceutically usable salts, solvates and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragxc3xa9es and hard gelatin capsules.
Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formula I and their pharmaceutically usable salts, solvates and esters can be used for the prophylaxis and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given above can be exceeded when this is shown to be indicated.
The invention is illustrated hereinafter by the examples, which have no limiting character.